Primary small cell carcinoma of the larynx. Survival time of 47 months. Case report.

Small cell carcinoma (SCC) of the larynx is a rare type of neuroendocrine carcinoma (NEC), few cases of which have been described in the literature. The prognosis for this type of carcinoma is poor, with a survival time typically not exceeding two years. We describe the case of a 54-year-old male patient with a primary tumor in the right ventricular band and a biopsy compatible with SCC. The patient underwent radiotherapy (RT) and concomitant chemotherapy (QT) and, after a relapse at 17 months, underwent total laryngectomy with bilateral neck dissection. The survival time was 47 months. Further studies are required to elucidate the possible causes of the better prognosis in some cases.

Diet-induced obesity may affect the uterine immune environment in early-mid pregnancy, reducing NK-cell activity and potentially compromising uterine vascularization.

OBJECTIVES: To investigate the effect of obesity in early-mid pregnancy on crucial pregnancy hormones and the uterine immune environment. BACKGROUND: Obesity impacts reproductive ability, adversely affecting conception and leading to complications in pregnancy. Obesity is often regarded as a stress state and an immune disease, both of which may contribute to pregnancy failure. We previously demonstrated that stress in early pregnancy greatly alters progesterone secretion. As progesterone is an immunomodulator, altered progesterone secretion may adversely modify the maternal immune system. In the current study, we test the hypothesis that obesity during pregnancy adversely alters the uterine immune environment. METHODS: An obese mouse model was created by feeding C57/BL6 mice on a high-fat (HF)/sugar diet for 12 weeks before pregnancy. Control mice were fed on lower-fat/sugar chow. Mice were mated, and on day 7.5 of pregnancy plasma progesterone and prolactin were measured by immunoassay. Cells from the uterus-draining inguinal lymph nodes were collected for analysis of the uterine immune response by flow cytometry. RESULTS: Diet-induced obesity increased the secretion of progesterone and altered a number of uterine natural killer (NK)- and T-cell responses. These included a marked reduction in the percentage of leucocyte-derived NK cells and reduced expression of interferon-γ (IFN-γ) in the NK cells compared with control mice. CONCLUSIONS: Maternal obesity, induced by an HF diet, may lead to a reduction in the expression of IFN-γ in NK cells. NK-cell-derived IFN-γ is reported to be involved in supporting uterine spiral artery remodelling. Thus, obesity in early pregnancy may compromise vascularization by reducing the expression of IFN-γ-positive NK cells. Furthermore, the expression of uterine CD8(+) cells was reduced in the HF diet-fed mice, suggesting obesity may adversely alter the maternal immune adaptation that is essential for effective pregnancy.

Prenatal stress enhances severity of atherosclerosis in the adult apolipoprotein E-deficient mouse offspring via inflammatory pathways.

Atherosclerosis is the underlying cause of cardiovascular disease and stroke. Endothelial cell dysfunctions are early events in atherosclerosis, resulting in the recruitment of circulating monocytes. The immune system can elicit an inflammatory response toward the atherosclerotic lesion, thereby accelerating lesion growth. Risk factors for atherosclerosis include hypertension, smoking, stress perception or low birth weight. As prenatal stress challenge decreases the birth weight and affects the offspring's postnatal immune response, we aimed to investigate whether prenatal stress contributes to the development of atherosclerosis in mice. Syngenic pregnant apolipoprotein E-deficient (apoE-/-) dams were exposed to sound stress on gestation days 12.5 and 14.5. The presence and size of atherosclerotic plaques in the offspring at the age of 15 weeks was evaluated by histomorphology, accompanied by flow cytometric analysis of the frequency and phenotype of monocytes/macrophages and regulatory T (Treg) cells in the blood. Further, cytokine secretion of peripheral blood lymphocytes was analyzed. In response to prenatal stress challenge, an increased frequency of large atherosclerotic plaques was detectable in apoE-/- offspring, which was particularly profound in females. Prenatal stress also resulted in alterations of the offspring's immune response, such as a decreased frequency of Treg cells in blood, alterations of macrophage populations in blood and an increased secretion of inflammatory cytokines. We provide novel evidence that prenatally stressed adult offspring show an increased severity of atherosclerosis. As Treg cells are key players in dampening inflammation, the observed increase in atherosclerosis may be due to the lack of Treg cell frequency. Future interdisciplinary research is urgently required to understand the developmental origin of prenatal stress-induced atherosclerosis. The availability of our model may facilitate and foster such research endeavors.

Fostering new investigators in Reproductive Immunology.

During the 8th European Congress of Reproductive Immunology, November 2010 in Munich, Germany, the European Society of Reproductive Immunology provided the opportunity for young investigators to present their work. Short talks from students and post-doctoral trainees were scheduled immediately after the keynote speakers in each session. The Society presented two "Young Investigator Awards" in basic science as well as in clinical application, sponsored by Elsevier. Here we present a summary of the nominees in a single article. The nominees were asked to give a guided interview to provide an insight into their motivation and career aspirations for the future. We hope that the Young Investigator Award might be an ongoing tool to motivate and encourage young investigators to stay in the field of reproductive immunology and to continue their research on the feto-maternal interface.

Stress increases VCAM-1 expression at the fetomaternal interface in an abortion-prone mouse model.

Sound stress exposure increases fetal loss via inflammatory pathways. Inflammation is known to up-regulate cell adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), which mediates the adhesion of leukocytes to the vascular endothelium. In this work, we studied the frequency of VCAM-1(+) vessels at the fetomaternal interface in stressed and non-stressed pregnant CBA/J female mice mated with DBA/2J (high fetal loss model) or BALB/c (low fetal loss model) males. The high fetal loss model had fewer large vessels on gestation day 6.5, and stress reduced the frequency of large vessels to a similar number in both high and low fetal loss models. In the high fetal loss model, however, the frequency of VCAM-1+ vessels was dramatically increased. This study shows that VCAM-1 expression is modulated by stress at the fetomaternal interface in abortion-prone cross-breeding.

Dehydroepiandrosterone and metformin regulate proliferation of murine T lymphocytes.

The aim of the present study was to assess the effect of dehydroepiandrosterone (DHEA: 10 microM) and metformin (10 microM and 100 microM) in regulating proliferation of cultured T lymphocytes. T cells were isolated from lymph nodes of prepuberal BALB/c mice. We found that DHEA, metformin and DHEA + metformin added to the incubation media diminished proliferation of T cells. The inhibition by DHEA was higher than that produced by metformin, while the combined treatment showed a synergistic action that allowed us to speculate distinct regulatory pathways. This was supported later by other findings in which the addition of DHEA to the incubation media did not modify T lymphocyte viability, while treatment with metformin and DHEA + metformin diminished cellular viability and increased both early and late apoptosis. Moreover, DHEA diminished the content of the anti-oxidant molecule glutathione (GSH), whereas M and DHEA + metformin increased GSH levels and diminished lipid peroxidation. We conclude that DHEA and metformin diminish proliferation of T cells through different pathways and that not only the increase, but also the decrease of oxidative stress inhibited proliferation of T cells, i.e. a minimal status of oxidative stress, is necessary to trigger cellular response.

The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice.

The aim of this study was to investigate the mechanisms by which N,N'-dimethylbiguanide metformin (50 mg/100 g body weight (BW) in 0.05 ml of water, given orally with a cannula) prevents the ovarian disorders provoked by the hyperandrogenization with dehydroepiandrosterone (DHEA) in prepuberal BALB/c mice. The injection of DHEA (6 mg/100 g BW in 0.1 ml of oil) for 20 consecutive days re-creates a mouse model that resembles some aspects of the human polycystic ovary syndrome (PCOS). The treatment with DHEA increased ovarian oxidative stress because it enhanced lipid peroxidation (LPO) and diminished both catalase (CAT) activity and glutathione (GSH) content. Therefore, the treatment with DHEA diminished both ovarian nitric oxide synthase (NOS) activity and prostaglandin E (PGE) production. When metformin was administered together with DHEA, the ovarian GSH content, NOS activity and PGE production did not differ when compared with controls. However, metformin was not able to prevent the effect of DHEA on ovarian LPO or CAT activity. Finally, DHEA increased the ovarian protein expressions of inducible NOS (iNOS), inducible cyclooxygenase (COX2) and the phosphorylated AMP-dependent kinase alpha (AMPK-alpha) (Thr172). Metformin administered together with DHEA was able to prevent the increase of ovarian iNOS and COX2 expressions and to enhance the activation of phosphorylated AMPK-alpha expression.

Metformin prevents embryonic resorption induced by hyperandrogenisation with dehydroepiandrosterone in mice.

The present study examined the mechanism by which metformin prevents dehydroepiandrosterone (DHEA)-induced embryonic resorption in mice. Treatment with DHEA (6 mg/100 g bodyweight, 24 and 48 h post implantation) induced 88 +/- 1 % embryonic resorption and the diminution of both serum oestradiol (E) and progesterone (P) levels. However, when metformin (50 mg/kg bodyweight) was given together with DHEA, embryo resorption (43 +/- 3% v. 35 +/- 5% in controls) and both serum E and P levels were not significantly different from controls. Glucose and insulin levels were increased in the DHEA-treated mice but when metformin was administered together with DHEA these parameters were similar to control values. Treatment with DHEA increased ovarian oxidative stress and diminished uterine nitric oxide synthase (NOS) activity; however, when metformin was administered together with DHEA, both ovarian oxidative stress and uterine NOS activity were not different from controls. Metformin treatment did not modify the percentage of CD4(+) and CD8(+) T cells from both axillar and retroperitoneal lymph nodes but prevented the increase of serum tumour necrosis factor +/- produced in DHEA-treated mice. These results show that metformin acts in DHEA-induced embryonic resorption in mice by modulating endocrine parameters, ovarian oxidative stress and uterine NOS activity.

Renal 99Tc(m)-DMSA SPET and planar imaging: are they really the same?

Previous studies have suggested that more defects are detected on SPET than on planar DMSA images. The aim of this study was to evaluate differences between planar and SPET imaging. Sixty-four kidneys from pyelonephritic patients were studied using both techniques. An automated algorithm for reorientation and centring of the SPET images was used to minimize inter-observer variability. Reduced uptake and contour defects showed different localization on planar and SPET imaging. Coincidence of defects on both types of image was low. We also noted a dependence on defect frequency content for detectability. Image contrast played a noticeable role in the detection of defects. Differences in contrast between SPET and planar images may be responsible for the variable success in the detection of defects. Contour defects are seen more frequently on tomographic slices, whereas reduced uptake defects are seen more frequently on planar images. A difference is also noted between the cortical and calyceal zones for differently contrasted lesions. SPET and planar DMSA images can potentially provide a different diagnosis of renal lesions.

Usefulness of 99Tcm-tetrofosmin scintimammography in palpable breast tumours.

The aim of this exploratory study was to assess the potential of discriminating malignant from non-malignant lesions using 99Tcm-tetrofosmin scintimammography in the detection of palpable breast tumours. Nine patients with palpable masses were studied; seven had malignant lesions and two had non-malignant lesions. All diagnoses were established by fine-needle aspiration (FNA) biopsy cytology. Each patient received 925 MBq (25 mCi) 99Tcm-tetrosfosmin intravenously. Planar prone views were acquired in the right lateral, left lateral and anterior positions, and the axillary regions were included in the field of view. Scintimammography showed focally increased tracer uptake in seven patients with a positive FNA result. The two patients with a negative FNA result showed no increased uptake. We suggest that 99Tcm-tetrosfosmin shows promise as a radiopharmaceutical in the detection and discrimination of the nature of palpable breast tumours. Larger studies are required to confirm these findings.

Kinetic study of the inhibition of rat liver ornithine decarboxylase by diamines; considerations on the mechanism of interaction between enzyme and inhibitor.

1. Partially purified rat liver ornithine decarboxylase is inhibited by several diamines including putrescine, 1,3-diaminopropane, cadaverine and p-phenylenediamine. 2. The inhibition is dependent on pH, being strong at pH above 8 and negligible below pH 6.5. 3. The kinetic study of the inhibition showed that while the aromatic diamine behaved as a simple competitive inhibitor, the aliphatic diamines presented a more complex pattern of inhibition in which two molecules of inhibitor might bind to the enzyme active site. 4. The Ki values for the different inhibitors were calculated and the degree of affinity for the enzyme was p-phenylenediamine greater than putrescine greater than cadaverine greater than 1,3-diaminopropane. 5. A molecular mechanism explaining how one or two molecules of inhibitor can bind to the enzyme is proposed.

Equilibrium between active and inactive forms of rat liver ornithine decarboxylase mediated by L-ornithine and salts.

The mechanisms controlling the activity of ornithine decarboxylase (ODC) are complex and only partly understood. This study shows that ODC can exist as two different aggregation states, that differ in catalytic activity, the dimeric form being active and the monomeric form inactive. While L-ornithine shifts the association-dissociation equilibrium to the dimeric form, salts produce an opposite effect leading to subunit dissociation. alpha-DFMO, an enzyme-activated irreversible inhibitor of ODC, does not react with the monomeric form and therefore the influence of substrate and salts on the aggregation equilibrium must be taken into account in titration experiments with alpha-DFMO of the total amount of ODC in tissue preparations.